Phosphatidylinositol 3,4,5-triphosphate (Ptdlns(3,4,5)P3), the end product of phosphatidylinositol 3-kinase (P13-K) phosphorylation of polyphosphoinositides, has recently been identified in islets. A rapid, transient increase in PtdIns (3,4,5)P3 levels, which peaks with the acute insulin response, can be induced by insulin secretagogues. We have analyzed the regulatory subunit os P13-K, p85a, as a candidate gene for the high prevalence of NIDDM in Pima Indians. A polymorphism at nucleotide 1020 (G-->A) which alters a Met to an lle at codon 326 in p85a was determined to be more frequent in Pimas (allelic frequency = 0.25) as compared to Caucasians (allelic frequency in CEPH = 0.17 and in Danes = 0.16). Analysis of this polymorphism in 950 full-blooded Pimas determined that the prevalence of NIDDM in individuals with the variant lle/lle genotype was lower (50%) compared to the prevalence in those with the Met/Met genotype (60%). This difference was due to the females in the study sample (n=550) where the prevalence of NIDDM in women with the common Met/Met genotype was higher (p<0.02). This difference was not observed in 400 Pima men (prevalence of NIDDM = 54% for both lle/lle and Met/Met). Women with the variant lle/lle genotype also had significantly higher acute insulin responses compared to women with the Met/Met genotype (p<0.008), which is consistent with the higher prevalence of diabetes observed in the latter group.